Use of lactulose in the treatment of autism

ABSTRACT

A treatment for autism in which an effective amount of lactulose is administered in order to bind excess ammonia in the gastrointestinal tract, the bloodstream, and the nervous system in order to prevent or reverse ammonia poisoning caused by the administration of certain antibiotics. Lactulose molecules in the colon are fermented by certain bacteria. The fermentation process lowers the colonic pH, and ammonia, in the form of ammonium ions, is used by the bacteria for amino acid and protein synthesis. This lowers the serum ammonia levels and reduces neurotoxicity.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/204,881, filed Aug. 8, 2011, now U.S. Pat. No. 8,673,877, issued onMar. 18, 2014; which is a divisional application of U.S. applicationSer. No. 12/049,613, filed Mar. 17, 2008, now abandoned, which is adivisional application of U.S. application Ser. No. 11/468,379, filedAug. 30, 2006, now abandoned, which claims the benefit of U.S.Provisional Application No. 60/712,551, filed Aug. 30, 2005. Each ofthese applications is incorporated in its entirety by reference.

FIELD OF THE INVENTION

The invention relates to a treatment for autism, and more particularly,to the use of lactulose in the treatment of autism.

BACKGROUND OF THE INVENTION

Autism is the most prevalent of a subset of disorders organized underthe umbrella of pervasive developmental disorder (PDD). Autism is aserious developmental disorder characterized by profound deficits inlanguage, communication, and socialization, resistance to learning, anddisplays of stereotypical behavior including perseveration. Known now asa spectrum disorder (ASD), it includes a myriad of behavioral,emotional, and physiological symptoms. Autism is a life-longdevelopmental disorder affecting as many as 1 in 500 children. Recentstudies have indicated that the prevalence is closer to 1 in 166 livebirths. The causes of this profound disorder are largely unknown. Recentresearch has uncovered pathology in the gastrointestinal tract ofautistic children. The pathology is reported to extend from theesophagus to the colon.

Lactulose is presently used in the treatment of constipation and hepaticencephalopathy. The efficacy of lactulose in these conditions is basedon its fermentation in the colon by certain bacteria and the increase ofthe biomass of these bacteria in the colon. The products of fermentationare mainly organic acids, such as lactic acid and small-chain fattyacids, which, by exerting a local osmotic effect in the colon, result inincreased fecal bulk and stimulation of peristalsis. The higher dosesused for hepatic encephalopathy lower the colonic pH, and ammonia, inthe form of ammonium ions, is used by the bacteria for amino acid andprotein synthesis. This lowers the serum ammonia levels and improvesmental function.

Increased or high levels of ammonia in the blood stream can producetoxicity to the cells of the body especially to the cells of the nervoussystem. This neurotoxicity can alter brain function and cause otherneurological diseases, including autism. Thus, decreasing the levels ofammonia in the blood would decrease the levels of ammonia in the brainthereby reducing the neurotoxic effects.

Certain drugs such as Augmentin® (amoxicillin+clavulanate potassium)have been known to leave an ammonia residue in the gastrointestinaltract. The increased levels of ear infections in children with autismand the use of Augmentin® to treat these and other infections makes thechild vulnerable to the potential buildup of ammonia in the digestivesystem as well as the blood, thus leading to a potential neurotoxicstate. By giving lactulose immediately following the administration ofAugmentin® or other ammonia producing substances, the potential for aneurotoxic disease is reduced.

It can be appreciated that lactulose has been used for years as atreatment for constipation and hepatic encephalopathy. However,lactulose has not previously been used as a treatment for autism orautism prevention. Presently, there exists no other pharmaceutical orbiological treatment for autism. Since there is no pharmaceutical orbiological treatment for autism, other than psychotropic medications forsymptoms, only behavioral and educational solutions have been offered.Behavioral treatments, such as applied behavioral analysis and TEACCH(Treatment and Education of Autistic and related CommunicationHandicapped Children) and others, have some value in the treatment ofthese children but do not address the physiological, specificallygastrointestinal, problems encountered by them.

What is needed, therefore, is a treatment for autism that works bypreventing the build up of ammonia in the gastrointestinal tract, thebloodstream, and the nervous system.

SUMMARY OF THE INVENTION

It is a goal of the present invention provide a treatment for autismthat addresses the physiological symptoms of the disorder.

It is another goal of the present invention to provide a treatment forautism that works by preventing the build up of ammonia in thegastrointestinal tract, the bloodstream, and the nervous system.

It is a further goal of the present invention to provide a treatment forautism that reverses the effects of ammonia poisoning on thegastrointestinal tract, the bloodstream, and the nervous system causedby certain antibiotics.

In one embodiment, lactulose is used to bind ammonia in thegastrointestinal tract, the bloodstream, and the nervous system.

The features and advantages described herein are not all-inclusive and,in particular, many additional features and advantages will be apparentto one of ordinary skill in the art in view of the drawings,specification, and claims. Moreover, it should be noted that thelanguage used in the specification has been principally selected forreadability and instructional purposes, and not to limit the scope ofthe inventive subject matter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram illustrating the mechanism of the function oflactulose in the colon.

DETAILED DESCRIPTION

Lactulose is a semisynthetic disaccharide comprised of the sugarsD-galactose and D-fructose. It is not found naturally. The sugars arejoined by a beta glycosidic linkage making it resistant to hydrolysis byhuman digestive enzymes. There is no disaccharidase in the microvillusmembrane of small intestine enterocytes that can hydrolyze lactulose;nor is the disaccharide absorbed from the small intestine. Lactulose is,however, fermented by a limited number of colonic bacteria. This canlead to changes in the colonic ecosystem in favor of some bacteria, suchas lactobacilli and bifidobacteria, which may confer some healthbenefits.

Lactulose is a solid substance that is very soluble in water and has asweet taste. It is sweeter than lactose but not as sweet as fructose.Lactulose is also known as 4-O-beta-D-galactopyranosyl-D-fructofuranose.Its molecular formula is C₁₂H₂₂O₁₁, and its molecular weight is 342.30daltons. The structural formula is:

Lactulose has an inhibiting action on ammonia production in the ileumand reduces the ammonia level in portal circulation. Referring to FIG.1, lactulose molecules pass through the stomach and ileum unsplit. Oncein the colon, the lactulose is fermented by certain bacteria, whichsupplies carbohydrates and energy. This results in an increase of thebiomass of these bacteria in the colon. The products of fermentation aremainly organic acids, such as lactic acid and small-chain fatty acids,which, by exerting a local osmotic effect in the colon, result inincreased fecal bulk and stimulation of peristalsis. The fermentationprocess lowers the colonic pH, and ammonia, in the form of ammoniumions, is used by the bacteria for amino acid and protein synthesis. Thislowers the serum ammonia levels and improves mental function.

It has been postulated that there is a relationship between the use ofthe antibiotic Augmentin® and autism. Many autistic children suffer fromchronic otitis media (ear infections) prior to age three. Otitis mediais generally by two strains of bacteria, Streptococcus pneumoniae andHemophilus influenzae. Augmentin® (amoxicillin-clavulanate) is afrequently prescribed antibiotic for this condition because it iseffective against both of these strains. However, the process ofmanufacturing Augmentin® involves the addition of urea or anotheravailable ammonia source to a fermentation broth. This additionalammonia represses the number of enzymes involved in the metabolism ofnitrogen, including urease, which catalyzes the conversion of urea toammonia and carbon dioxide. Thus, there is the possibility of ureaand/or nitrogen poisoning.

Urea and/or nitrogen poisoning has a two-fold effect in humans: 1) aneurotoxic effect on brain tissue and 2) a corrosive effect on thedigestive tract, specifically damage to the secretory cells of the smallintestine, due to the highly alkaline nature of NH₃. Signs of ureapoisoning include colic, bloating, diarrhea, muscle tremors, difficultywith coordination, weakness, and poor appetite.

In a study conducted by the inventor, 206 children with autism notrelated to a known genetic condition, birth trauma, or knownneurological disease were examined and a detailed case history wasobtained. The 206 children tested had a mean number of 9.96 instances ofotitis media with a standard error of the mean of ±1.83. Thisrepresented a sum total for the 206 children under age three of 2052bouts of otitis media. These children received a mean number of 12.04courses of antibiotics with a standard error of the mean of ±0.13. Thetotal number of courses given to all of the children in the study was2,480. Of those courses, 893 were Augmentin®, with 362 of those coursesof Augmentin® being administered to children under age one.

The increased levels of ear infections in children with autism combinedwith the use of Augmentin® to treat these infections has the potentialto make these children vulnerable to the buildup of ammonia in thegastrointestinal tract, the bloodstream, and the nervous system, leadingto a neurotoxic state. By administering lactulose subsequent to a courseof treatment with Augmentin® or other antibiotics that leave an ammoniaresidue in the gastrointestinal tract, the potential for a neurologicaldisease, such as autism, is reduced.

In one embodiment of the present invention, the treatment has aformulation of 0.4 g/kg lactulose and 0.1 g/kg mannitol. In anotherembodiment, the treatment has a formulation of 0.3 g/kg lactulose. Ineither embodiment, the treatment is administered two to five times perday. The lactulose may be administered in the form of a powder, liquidsolution, or syrup.

The foregoing description of the embodiments of the invention has beenpresented for the purposes of illustration and description. It is notintended to be exhaustive or to limit the invention to the precise formdisclosed. Many modifications and variations are possible in light ofthis disclosure. It is intended that the scope of the invention belimited not by this detailed description, but rather by the claimsappended hereto.

What is claimed is:
 1. A method for treating an individual diagnosed with an autistic disorder, the method comprising administering a therapeutically effective amount of lactulose and mannitol to the individual, wherein administration of the lactulose follows administration of an antibiotic, and wherein administration of lactulose increases the number of lactobacilli and bifidobacteria in a gut flora.
 2. The method of claim 1, wherein the individual has a gastrointestinal disorder, a neurological disorder, or a combination thereof.
 3. The method of claim 1, wherein the lactulose is administered in an amount of about 0.4 g/kg lactulose per dose.
 4. The method of claim 1, wherein the lactulose is administered in an amount of about 0.3 g/kg lactulose per dose.
 5. The method of claim 1, wherein the lactulose is administered approximately two to five times per day.
 6. The method of claim 1, wherein the lactulose is administered in a form selected from the group consisting of a powder, a liquid solution, a syrup, and a combination thereof.
 7. The method of claim 1, wherein a level of ammonia is decreased in the blood of the individual.
 8. The method of claim 1, wherein a level of ammonia is decreased in the gastrointestinal tract of the individual.
 9. The method of claim 1, wherein a level of ammonia is decreased in the nervous system of the individual.
 10. The method of claim 1, wherein the lactulose reverses ammonia poisoning caused by the administration of antibiotics that leave a residue in the gastrointestinal tract of the individual.
 11. The method of claim 1 wherein the mannitol is administered in an amount of about 0.1 g/kg mannitol per dose.
 12. The method of claim 1, wherein administration of the lactulose immediately follows administration of the antibiotic.
 13. The method of claim 1, wherein the antibiotic is amoxicillin-clavulanate. 